PROJECT SUMMARY: Our application is in response to RFA-AA-18-009 Medications Development for the Treatment of Alcohol Use Disorder. Only three pharmacotherapeutic treatments for Alcohol Use Disorder (AUD) are FDA approved and none are widely used (<10% of AUD patients) or show a strong effect to reduce risky- or dependence-based drinking in the long-term (<20% see sustained decreased drinking outcomes). Unfortunately, approximately 10% of the population suffers from AUD and over 5% of all medical morbidities share risky ethanol consumption as an underlying issue. As a consequence, intoxication, in general, and ?alcohol addiction? (severe AUD), in particular, are important clinical problems. Given the limited pharmacotherapeutic choice, there is a compelling need for continued development of new treatments across the AUD spectrum (mild to severe DSM-V classification). In fact, improved treatments targeting high alcohol consumption and withdrawal-related symptoms are desirable as precipitating withdrawal can be a medical emergency with risk for death. To date, drugs targeting drinking do not protect against withdrawal, and drugs used to reduce withdrawal symptoms are often co-addictive with alcohol. We recently showed that tetracycline analogs were preclinically efficacious to reduce high alcohol consumption, withdrawal symptoms and alcohol-mediated pain sensitization and now have exciting preliminary data showing efficacy for an improved chemically modified minocycline (CMM). In collaboration with the NIAAA Division of Medications Development, we propose to prepare our CMM analog for IND approval by the FDA. Additional oversight is provided by an external advisory committee of Drs. Adron Harris and Robert Messing. Our preliminary data illustrated a reduction of alcohol consumption in two mammalian species. We will complete two aims addressing approval of our CMM as an IND by the FDA using murine and porcine AUD models as appropriate: 1) C57BL/6J mouse ?binge? (acute) and ?dependence? (chronic) models, which importantly reach pharmacologically relevant blood alcohol levels, and 2) our new voluntary, high alcohol preference, porcine (pig) model. AIM 1: to complete detailed pharmacokinetic evaluation of CMM for drug absorption, distribution, metabolism and excretion (ADME). AIM 2: to determine potential acute and chronic toxic effects of CMM, including carcinogenicity, genotoxicity, immunotoxicity, tissue damage and effects on reproduction. Negative effects will be addressed using a medicinal chemistry approach with changes made as necessary. At this time, we have six other CMM analogs, which can be used as substitutes. Future Phase I plans include testing in AUD patients, first in a small trial with our TTUHSC Clinical Research Institute and then in cooperation with the NIAAA Clinical Investigations Group (NCIG). Impact: The development of a drug without addiction potential that targets several important aspects of AUD symptoms has critical advantages over current therapies.